throbber
-·--'-____ ..--
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BD1 CIP FWC III
`
`No.
`
`For
`
`Art Unit
`
`Examiner
`
`Sherie L. Morrison, et al.
`
`07/893,610
`
`June 3, 1992
`
`RECEPTORS BY DNA SPLICING
`AND EXPRESSION
`
`1806
`
`T. Nisbet
`
`August 23, 1993
`
`Hon. Commissioner of Patents
`and Trademarks
`Washington, D.C. 20231
`
`RESPONSE UNDER 37 C.F.R. §1.115
`TO EXAMINER'S ACTION
`
`Sir:
`
`..::;:
`
`following amendments to the pending claims:
`
`Applicants respectfully request entry of the
`
`(Thrice amended) A method for producing a
`
`,.
`,1'
`ibody having a heavy chain and a light chain
`
`[two
`
`which comprises the steps of:
`
`of the anti
`
`chain [subunit] being
`
`a chain [subunit] othe
`
`the first chain (subunit) and
`
`said first and second
`
`bein either the heav chain or
`
`the light chain; and
`
`(c)
`
`the cell in a nutrient medium, so
`
`that the cell expresses the first and second DNA sequences
`
`and the resultant chains [su~ nits) are intracellularly
`
`assembled together,to
`
`which is then
`
`070 rl 09/13/93 07893610
`
`1 103
`
`330a00 CK
`
`Mylan v. Genentech
`IPR2016-00710
`Merck Ex. 1112, Pg. 1
`
`

`

`.
`•
`• .~.
`~-~:~<~·.... 1!c.'"::~~
`d in a
`.
`apable of specifically binding to
`
`•
`
`-~:
`
`c
`
`seer
`
`ant
`
`.
`
`claim 39 (43]
`
`not endogenously produce
`
`in
`
`(Amended)
`
`claim 4 I
`
`(43] wherein the cell
`
`[only] an
`
`immunoglobulin
`
`munoglobulin heavy chain
`
`functional antibody having a heavy chain and a light chain
`
`[two subunits], whic comprises the steps of:
`
`A method for producing a
`
`(a)
`
`transf ~ding a non-antibody producing
`
`~ammalian;!~~l~h !d) cell with a plasmid comprising a
`
`antibody and a second DNA sequence coding for a
`
`for a first chain (subunit]
`
`antibody, said second
`
`first chain (subunit] and said first and second chains
`
`bein either the heav
`
`li ht chain; and
`
`(b) maintaining
`
`nutrient medium so
`
`that the cell expresses
`
`first DNA sequence and
`
`said second DNA sequence
`
`the resultant chains
`
`[subunits] are intracellu arly assembled together to
`
`form the antibody which
`
`then secreted in a form
`
`capable of specifically
`
`ding to antigen.
`
`2
`
`Merck Ex. 1112, Pg. 2
`
`

`

`•
`
`~_)_
`
`,li • .P
`Please add the following claim~
`
`, •
`
`. ~
`
`recited in claim 39 wherein
`
`e
`
`cell is
`
`A method
`
`cell is transfected via
`
`cell
`
`in claim p-4 wherein the
`'?--
`via calcium phosphate precipitation.
`
`~:-~
`
`cell is a
`
`i
`\-,
`cell is
`
`in claim ?'4 wherein the
`
`·:~;
`
`:;(
`
`recited in claim ?'4 wherein the
`),.,..
`
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`Ga:.
`//
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`cell is a murine myeloma cell.
`
`A
`
`in claim
`
`/ wherein the
`?'0
`/,.~;
`
`A method
`
`\'b
`,.2~.
`;
`cell does not
`
`chains.
`
`r
`\ [\
`63.
`/
`cell is a murine
`
`A
`
`method
`
`as
`
`,
`·r
`~·0 6A. A method as
`I I
`r
`cell endogenously
`
`claim ~·4 wherein the
`_:.:;~
`immunoglobulin
`
`6:f wherein the
`
`:'
`
`9'2,..--
`light chain or
`
`an
`
`but not both.
`
`3
`
`Merck Ex. 1112, Pg. 3
`
`

`

`: . •
`
`('
`
`• A method
`~~,6. A method as recited in claim 54 wherein the
`
`"? \' 6p.
`l
`t,r-.
`cell is a murine
`
`as
`
`in claim 64 wherein the
`
`antioody is a
`
`'
`\ ..--
`antibody having a variable region
`
`'
`
`substantially
`
`same as that found in a first mammalian
`
`a constant region substantially the same
`
`as that found in a second mammalian source, said second
`
`mammalian source
`
`a mammalian species other than
`
`!that of the first
`
`source.
`
`/ '
`1-7/67.
`having a heavy chain
`
`steps of:
`
`tor producing·a functional antibody
`
`d a light chain which comprises the
`
`(a) maintaini g in a n~ri([t medium a non(cid:173)
`
`antibody producing mammal'an)j!lJJ/, ~1lo cell having been
`
`transfected with a
`
`A sequence coding for a first
`
`chain of the
`
`second chain
`
`DNA sequence coding for a
`
`second chain being a
`
`chain other than the first ch
`
`first and second
`
`chains being either the heavy
`
`or the light chain;
`
`(b)
`
`expressing from
`
`cell the heavy chain and
`
`the light chain functionally asse bled together to form said
`
`antibody which is then secreted in a form capable of binding
`
`antigen; and
`
`(c)
`
`recovering said
`
`/J l\
`
`./">"
`
`'
`
`f>i" A method as recited in
`cell is transfected via
`
`{
`
`•
`
`6:1- wherein the
`'
`.. t
`via calcium phosphate precipitation.
`
`~-
`
`4
`
`Merck Ex. 1112, Pg. 4
`
`

`

`• 70.
`
`c~
`
`......
`
`/
`ce11 is a mye1oma
`
`r~ci~~d in c1aim 67 wherein the
`
`~~ <'""
`
`.
`
`in c1aim 67 wherein the
`..
`
`///~·
`A
`
`"1\ l'l._.,.. ":l'2.
`j
`t
`ce11 1~ a murine mye1oma
`
`recited in c1aim ;prwherein the
`tZ: ~
`
`11.
`
`73~ A method as
`
`_fY7 wherein the
`
`ce11 dcles not
`
`chains •
`
`immunog,,Q obu1 in
`
`ce11 is a murine
`
`as recited in c1aim 73 wherein the
`:(r' :, »i
`c.::..-
`
`75. A method as
`
`ce11 endogenous1y produces
`
`~3
`'lfght chain or
`
`an immunog1obu1in
`
`both.
`
`t
`
`·"'~..,/
`£
`. ''
`
`.
`
`.
`.
`
`'
`
`~/\ _,_
`--
`
`76. A method. as
`
`c1aim 75 wherein the
`'r -~ :~
`
`antibody is a chimeric
`
`method as
`
`in c1aim 6i wherein the
`.v
`<""f<'?>
`. "
`h~ving a variab1~ region
`
`substantia11y the same
`
`ound in a first mamma1ian
`
`as that found in a second mamma1ia
`
`source, said second
`
`,,mamma1ian source being from
`f.
`
`that of the first mamma1ian source.
`
`ian species other than
`
`P1ease cance1 c1aim~51.
`
`-----
`
`5
`
`Merck Ex. 1112, Pg. 5
`
`

`

`-·
`
`REMARKS
`
`This application claims a method for producing a
`
`functional antibody and is related to co-pending application
`
`Serial No. 07/771,410 which claims functional antibodies
`
`produced by the method of the instant application.
`
`In Paper
`
`No. 15 of the '410 application, an Advisory Action dated
`
`May 12, 1993, the Examiner noted that n[a)pplicants•
`
`arguments may be persuasive with respect to method, but not
`for product •.. " 1 That Adviso·ry Action was written
`
`subsequent to the outstanding Office Action in the instant
`
`application. Applicants agree that the record of the 1 410
`
`application, including the arguments th~t applicants have
`
`presented therein, supports the patentability of the pending
`
`method claims. Noting the Examiner's statement in the
`
`related application; and in an effort to make a complete
`
`record and to ~pecifically address the points raised by the
`
`Examiner in the outstanding Office Action, applicants make
`
`the following response.
`
`On January 3, 1992, applicants filed the Rule 131
`
`Declarations of Dr. Sherie L. Morrison and Dr. Vernon T. Oi
`
`to swe.ar behind the Ochi et al. reference.
`
`In order to
`
`clarify the role of each of the inventors, applicants submit
`
`herewith the Rule 131 Declaration of Leonard A. Herzenberg.
`
`Enablement
`
`In paragraph 16 of the Office Action, the Examiner
`
`has rejected the pending claims as enabling only the
`
`expression of na chimeric polypeptide which is a subunit of
`
`an immunoglobulin molecule", for reasons stated in papers 5,
`
`7 and 10. That reasoning found that claims drawn to a
`
`1
`The claims in the related application were
`rejected on legal grounds regarding patentability
`requirements specific to product-by-process claims.
`
`6
`
`Merck Ex. 1112, Pg. 6
`
`

`

`,.
`
`•:.
`
`•
`
`method for producing a "receptor" were too broad and could
`
`include the production of Major Histocompatibility complex
`
`antigens and T-cell receptors. However, applicants have
`
`requested the cancellation of claims 49-51 that contain that
`
`broader language. That cancellation obviates this
`
`rejection. The remaining claims cover a method for
`
`producing a "functional. antibody". Functional antibodies
`
`are disclosed as the product of the method described in the
`
`present application and are fully supported by the
`
`specification.
`
`The Examiner has also made an enablement rejection
`
`based on information in the Rule 131 Declaration of Dr.
`
`Morrison.
`
`In respoDse to the Examiner's invitation in the
`
`Office Action, applicants submit the following explanation
`
`to show enablement of the instant invention in non-antibody
`
`producing mammal.ian cel.l.s.
`
`The Examiner's conclusion that the invention is
`
`-·
`
`not enabled for any cell ~ines other than the particular
`
`cell line used is based on the erroneous premise that onl.y 1
`
`in 4 of the experiments performed is operative to show
`
`antibody binding. The declaration of Dr. Morrison submitted
`
`previously to show diligent reduction to practice details
`
`the work done after transforming the J558L cells.
`
`In
`
`paragraph 10 of that declaration Dr. Morrison described the
`
`performance of SDS gel electrophoresis on the expression
`
`product of the transfected J558L cells. That gel confirmed
`
`that appl.icants had successfully obtained ful.l.y assembl.ed
`
`antibody molecules.
`
`Paragraph 11 of that declaration describes
`
`Dr. Morrison's attempt to show that those antibodies were
`
`capable of specific binding, but the substance that she was
`
`using to radio-label the antibodies was of poor quality.
`
`Therefore that assay was unsuccessful due to chemical
`
`7
`
`Merck Ex. 1112, Pg. 7
`
`

`

`problems with the analytical tool, not_because of any
`
`problem with the expression product.
`
`When Dr. Morrison retested the antibody with a new
`
`preparation of the radio-label, the ELISA assay successfully
`
`showed binding activity as described in paragraph 12 of her
`
`declaration. Thus, applicants successfully showed binding
`
`the first time they used an appropriate test. An ELISA test
`
`is what Cabilly (A and R} relied on to show antigen binding.
`
`However, applicants believed that a more stringent and
`
`reliable test for binding should subsequently be performed
`
`using a PC column.
`
`Dr. Morrison's first attempt to show binding with
`
`a PC column was not successful as described in Paragraph 13
`
`of the declaration. To investigate this, Dr. Morrison ran
`
`another ELISA assay and discovered that the transfected cell
`
`-::.::-
`
`line had likely lost the ability to express the transfected
`
`kappa light chain gene. The loss of transfected gene
`
`~k
`
`expression often occurs and Dr. Morrison reacted by re(cid:173)
`
`transfecting the kappa light chain gene as described in
`
`paragraph 15 of her declaration. After re-transfecting the
`
`exogenous light chain gene, the analysis of the expression
`
`product with the PC column described in paragraph 15
`
`suggested specific binding.
`
`In order to obtain a more certain result, Dr.
`
`Morrison changed the selection marker on the light chain
`
`vector and re-transfected the cells with that new vector as
`
`described in paragraph 18 of her declaration. The suggested
`
`mutation mentioned in paragraph 18 is the same mutation
`
`mentioned in paragraph 14, namely that the cell line had
`
`lost its ability to produce the transfected kappa light
`
`chain gene.
`
`In Paper No. 26 the Examiner states that nthe
`
`J558L cell line underwent some unexplai~ed mutation ...
`
`which resulted (in] the single chain loss mutant becoming a
`
`8
`
`Merck Ex. 1112, Pg. 8
`
`

`

`• •• i'
`
`double chain loss mutant." The mutation that Dr. Morrison
`
`referred to in her declaration was the loss of expression of
`
`the exogenous kappa light chain gene, not the loss of
`
`expression of the endogenous lambda light chain gene2
`
`•
`
`Because there was no suspi~ion of a mutation in the
`
`endogenous gene and because antigen binding by the
`
`expression product of the transfected genes was· shown via
`
`ELISA both before and after the re-transfection of the kappa
`
`light chain gene, the expression of antibodies was not a
`
`peculiarity of any mutation in'th~ cell line with which Dr.
`
`Morrison was working.
`
`As the Examiner points out, the phosphate buffer
`
`may have been the reason no binding was obtained in the
`
`first run with the PC column. Elimination of that buffer as
`
`=~~
`
`described in paragraph 18 removed an impediment to specific
`
`antigen binding and allowed Dr. Morrison to demonstrate
`
`again that she had obtained antibodies capable of specific
`
`binding.
`
`Because applicants successfully showed antigen
`
`binding with the PC column and with ELISA both before and
`
`after the suspected loss of expression of the,transfected
`
`kappa chain, it is simply not the case that only 1 of 4
`
`experiments is operative in the instant claims. Applicants
`
`submit that the repeated positive results rebut the basis
`
`for asserting a lack of enablement of other non-producing
`
`cell lines.
`
`2
`The J558L cell line did not become a double chain
`loss mutant. To make certain that the record is·clear,
`applicants define a non-antibody producing cell as one that
`does not express, secrete and assemble functional
`antibodies. Such a cell is not necessarily a double chain
`loss mutant; the cell may express and secrete a single
`immunoglobulin chain.
`
`9
`
`Merck Ex. 1112, Pg. 9
`
`

`

`• ~-·-
`
`. .
`
`Obviousness
`The pending claims stand rejected under 35 u.s.c.
`§ 103 as obvious over Cabilly (L, R or 2A) or Boss {2B) in
`
`view of Gillies{S). Applicants respectfully traverse this
`
`rejection.
`
`The Examiner suggests that Cabilly's teaching of
`
`producing two immunoglobulin chains by expressing two
`
`exogenous genes in bacteria, and Cabilly's mention of
`
`mammalian host cells, taken together-with Gillies'
`
`production of a single exogenous chain that assembles with
`
`endogenous chains to form a tetramer, renders applicants'
`
`invention obvious. However, at the time of the invention
`
`many additional circumstances precluded one who would try to
`
`combine these teachings from having a reasonable certainty
`
`that they would succeed in producing functional antibodies.
`
`A basis of the obviousness rejection is that
`
`mammalian systems were known to functionally express
`
`exogenous immunoglobulin genes. Applicants agree that the
`
`prior art did teach transfecting and expressing a single
`
`exogenous gene coding for one chain of an immunoglobulin in
`
`a mammalian cell which expresses an endogenous gene coding
`
`for another immunoglobulin chain. Gillies et al., Cell, 33,
`
`pp. 717-28 (1983); Oi et al., Proc. Natl. Acad. Sci. USA,
`
`80, pp. 825-29 (1983); Rice et al., Proc. Natl. Acad. Sci.
`
`USA, 79, pp. 7862-65 (1983). However, the endogenous-
`
`exogenous approach followed in each of these references
`
`produced tetramers that were not functional antibodies
`
`because the binding sites of the exogenous immunoglobulin
`
`chains were not complimentary to the binding sites of the
`
`endogenous chains.
`
`Indeed, prior to applicants' invention,
`
`no exogenous immunoglobulin gene had been functionally
`
`expressed.
`
`10
`
`Merck Ex. 1112, Pg. 10
`
`

`

`•
`
`Further, prior to the present invention, it was
`
`not even believed that the endogenous-exogenous approach
`
`would always produce an immunoglobulin, let alone one that
`
`binds an antigen.
`
`In Oi, a ~ouse myeloma cell supported
`
`expression of a transfected immunoglobulin gene. However, a
`
`rat myeloma cell line which expresses and secretes an
`
`endogenous light chain, when treated in the same manner as
`
`the mouse myeloma, did not support expression of a
`
`transfected immunoglobulin chain gene.
`
`In sum, prior to the present invention, the art as
`
`a whole taught that a non-producing cell would not
`
`necessarily express a transfected exogenous immunoglobulin
`
`chain gene. Thus, applicants certainly would not have had a
`
`reasonable expectation that such a cell would successfully
`
`express, secrete and assemble the· product of that first
`
`exogenous gene with the product of a second exogenous gene.
`
`Consequently, applicants' invention is not obvious in view
`
`of the prior art.
`
`Also in paragraph 17, the Examiner states that the
`
`instant claims cannot be given the August 1984 priority
`
`date. On that date the first application in the chain that
`
`led to the present application was filed. It disclosed the
`
`production of functional antibodies by co-transfecting a
`
`mammalian cell with exogenous DNA.
`
`In August 1987 a CIP
`
`application (Serial No. 07/090,669) was filed in which
`
`material was added to the·specification.to specifically
`
`address the production of intra-species chimeric antibodies.
`
`Additional claims were filed based on that new matter.
`
`However, on March 22, 1991, the new claims to
`
`intra-species chimeras were cancelled. The new material
`
`added to the specification in 1987 is not relied on in any
`
`way to support the instant claims. The new disclosure in
`
`the specification did not narrow the invention such that
`
`11
`
`Merck Ex. 1112, Pg. 11
`
`

`

`,_
`
`•
`
`.. --
`
`•
`
`applicants are now trying to avoid it; the new disclosure
`
`was additive and applicants are no longer seeking claims
`
`based on the new matter.
`
`Because the instant claims are fully supported by
`
`material originally disclosed in the parent application,
`
`they are entitled to the benefit of the August 1984 filing
`
`date. Accordingly, for reasons of record in previously
`
`filed papers, Boss(S) is not prior art to applicants'
`
`invention.
`
`In response to the.Examiner's invitation at the
`
`end of paragraph 17 on page 4, and to show unexpected
`
`results--a secondary consideration in an obviousness
`
`determination--, applicants submit with this response a Rule
`
`132 Declaration of Sherie L. Morrison. The Federal Circuit
`
`requires the evaluation of secondary considerations
`
`including unexpected results before the issue of obviousness
`
`is decided. Stratoflex, Inc. v. Aeroguip Corp., 713 F.2d
`
`1530, 1538 (Fed. Cir. 1983). Dr. Morrison's declaration
`
`explains laboratory data that establish an unexpectedly high
`
`yield of functional antibody and explains why that high
`
`yield obtained from the J558L cell line, although
`
`unexpected, is predictive of the same high yield in other
`
`mammalian cell lines.
`
`Applicants' initial analysis of the expression
`
`product of their co-transformed cells was performed without
`
`attention to maximizing yield, but rather merely to
`
`demonstrate specific binding. · Non~theless, that analysis
`
`demonstrated an unexpectedly high 32% yield of active,
`
`assembled antibody.
`
`(Morrison Declaration, ! 5, submitted
`
`herewith.)
`
`In fact, that yield is likely a significant
`
`underestimate of the amount of correctly assembled antibody
`
`produced.
`
`(Morrison Declaration, ! 8.)
`
`12
`
`Merck Ex. 1112, Pg. 12
`
`

`

`•
`
`-. •
`
`Cabilly's denaturation/renaturation approach to
`
`"recombination" of light and heavy chains resulted in an
`
`extremely low level of antibody formation -- only 0.76% of
`
`the chains are reported as having "recombined" to form
`
`antibody. Applicants achieved a yield that is over 42 times
`
`greater than the amount of active antibody that Cabilly
`
`reported and, therefore, is unexpectedly high when compared
`
`with Cabilly's .76% yield.
`
`One might expect an improved yield when expressing
`
`a mammalian gene in a mammalian environment as applicants
`
`did. Even expecting to double the yield might be
`
`reasonable. However, applicants have obtained a wholly
`
`unexpected improvement in yield that is 42 times the yield
`
`cited in the Cabilly patent. This result is of both
`
`statistical and practical significance.
`
`(Morrison
`
`Declaration, ~~ 9-10.)
`
`Even Cabilly's .76% yield may be an overstatement.
`
`Cabilly's 0.76% yield is based on an estimate of the levels
`
`of heavy and light immunoglobulin chains in the reaction
`
`mixtures and on an antigen binding assay. Not only is this
`
`calculated yield dubious by virtue of its reliance on an
`
`estimate with unknown associated error, but the calculation
`
`also used as a background number the binding measured for
`
`cells producing light chains only. A more accurate
`
`background number to correct for non-specific binding would
`
`have been the antigen-binding, for cells producing only heavy
`
`chains because it has been found that heavy chains alone
`
`will bind antigen in the absence of a complementary light
`
`chain. Ward et al., Nature, vol. 341, pp. 544-46 (1989).
`
`That number would likely have been much higher than the
`
`light chain background number and would have resulted in a
`
`lower percent yield. Even given this potential for
`
`overestimating percent recombination, Cabilly calculated
`
`13
`
`Merck Ex. 1112, Pg. 13
`
`

`

`•
`
`•
`
`obtaining only a fraction of one percent of the antibody
`
`protein in active form.
`
`Whether or not Cabilly's yield is an accurate
`
`estimate, applicants• yield is so much larger as to be an
`
`unexpected result. Such results constitute a secondary
`
`consideration weighing against a finding of obviousness.
`
`The Examiner has invited applicants to clarify the
`
`record as to why the unexpected yield of a single cell line
`
`would be predictive of all cell lines. As set forth in Dr.
`
`Morrison's declaration (,, 11-13), co-expression of
`
`exogenous genes in J558L, a cell that did not differ from
`
`other mammalian cells in its ability to express endogenous
`
`genes, would be predictive of similar co-expression of
`
`exogenous genes in those ·other mammalian cells .. While
`
`applicants have discussed the unpredictability of whether it
`
`would work'at all to produce functional antibodies by co(cid:173)
`
`expression, applicants have not stated any reason that once
`
`co-expression was found to work, other similar cells that
`
`_;::--.7;
`
`are similarly transfected would behave differently.
`
`Indeed,
`
`the Rule 132 Declaration of Dr. Morrison states reasons to
`
`believe that other mammalian cells would behave similarly.
`
`The non-obviousness of applicants• approach is
`
`also evidenced by the reaction of those skilled in the art.
`
`In 1984, Michael Boss congratulated one of the present
`
`inventors for, in essence, beating him to the production of
`
`functional antibodies by using eukaryotic cells instead of
`
`bacteria.
`
`(Morrison Declaration, , 14.) Such praise for
`
`the invention is another secondary consideration that
`
`supports a finding of nonobviousness.
`
`Interconnect Planning
`
`Corp. v. Feil, 774 F.2d 1132, 1143-44 (Fed. Cir. 1985).
`
`In view of the foregoing, applicants believe that
`
`the pending claims are in condition for allowance.
`
`14
`
`J
`
`Merck Ex. 1112, Pg. 14
`
`

`

`•
`
`•
`
`Accordingly, entry of the present amendment and allowance of
`
`the claims are requested.
`
`Respectfully submitted,
`
`E~~uLehAo. 27,459)
`
`Vicki s. Veenker
`
`{Reg. No. 34,269)
`
`Attorneys for Applicants
`cjo FISH & NEAVE
`1251 Avenue of the Americas
`New York, New York 10020
`{212) 596-9000
`
`I Hereby Certify that thls
`Correspondence I$ being
`Deposited with the U.S.
`Postal Service as First
`Class Mall 1n an Envelope
`Addressed to: Commissioner
`of P~tents and Trademarks.
`Washington. D.C. 20231. on
`/Juqu5 t c2 .:;: t£9 -t
`Dalene Qulachon-Rosen.
`Name of Person Signing
`_ /J ..
`~ObUa.~A l~
`Signature of Person S!~nfn'!
`
`15
`
`Merck Ex. 1112, Pg. 15
`
`

`

`•· •\'
`
`,_ ;
`
`'
`
`r
`
`BD1 CIP FWC II DIV 1
`
`IN THE
`
`PATENT AND TRADEMARK OFFICE
`
`Applicants
`
`Serial No.
`
`Filed
`
`For·
`
`Group
`
`Sherie L. Morrison, et·al:
`
`·0~/893,610
`
`.June 3, 1992. · .. ·
`
`.. RECEPTORS .'BY DNA SPLICING ·
`,,
`:,, _ _.:~v-~AND. ·.EXPI_mss~ON
`
`_;
`
`'l806
`
`Examiner
`
`~ . .
`
`'~
`
`T . .' Nisb:et · ..
`
`Hon. Commissioner of Patents
`and Trademarks
`Washington, D.C. 20231
`
`DECLARATION OF LEONARD A·. fiERZE~BERG
`PURSUANT TO 37 C.F.R. §'1.131
`
`I, LEONARD A. HERZENBERG,· d~clare that:.
`
`I am a·co-inventor in the above-identified
`
`patent application.
`
`2 .•
`
`I am aware-of the ~~liowing p~biication by
`
`Ochi et al., "Functional Immunoglobu_lin M Production After
`.
`.
`Transfection of· Cloned 'rmmun9globulin Heavy And Light Chain
`. .
`.
`Genes Into Lymphoid Cells",_ Proc .. Nat'l Acad. ~ci. ·usA, vol.
`
`~
`
`80, pp. 6351755 (Oct. 1983), ;and am informed an~ believe
`
`that it was_ mailed to subscribers of the journal irr which it
`
`Merck Ex. 1112, Pg. 16
`
`

`

`,.,
`...r
`
`~ •;'
`/
`
`""i
`
`'~ •
`
`,(_
`
`f
`
`!:
`
`,,
`
`was published on October 19, 1983. ~ copy of that article
`
`is attached hereto as Exhibit A.
`
`3.
`
`I make this declaration to establish, when
`
`read in conjunction with the· ·declara.tions ·of Sherie L.
`
`Morrison and ve·r.pon T. 0~, my 'co-inveri'tors, the c~nception
`
`of producing a 'fu~cti9~a1' a~~ibq~y from a· ~r~nsfected
`
`mammalian cell prior to· the October 19, 1983 effective date
`of the Ochi .. refer:~nce and .. t~,·· e~ta-biish the-~diligent
`
`...
`
`~
`
`'
`
`'
`
`'
`
`.,
`
`.
`
`..
`
`reduction to practice of the invention from a time prior t'o
`
`.said date.
`
`4.
`
`Cqnception of the invention is evfdenced by
`
`the gran~_applica~ion that I submitted to Becton Dickinson
`
`with Vernon T. Oi and by_ the grant application·tha~ Sherie
`
`r;. Morrison submitted to the American Cancer Society·. The
`
`dates.of those app+~cations.are prior to October 19, 1983.
`.
`.
`'
`Copies of the pertinent portions of. the applications are
`
`attached·as ExHibit Band Exhibit c respectively.
`
`5.
`
`Prio.r to Octobe·r 19, _1983,. Dr. Oi was
`
`.• ...,
`
`employed in my laboratory at Stanford University as a post(cid:173)
`
`D6ctoral scientist.· Dr._.Oi ·and I had conceived the. idea of
`
`producing chimeric ant.ibod~es and Dr. Oi was engaged· in
`
`laborat~ry work under my supervision that resulted .. in the
`
`construction of a vector (designated· HuK) containing.a gene
`
`·coding for the light chain of an antibody. Evidence of this
`
`work ·is contained in the copies of pages from Dr. Oi's
`
`2
`
`Merck Ex. 1112, Pg. 17
`
`

`

`• ,r
`
`laboratory notebook attached hereto as Exhibit D. Those
`
`pages· are dated prior to october 19, 19~3. Dr. Oi also
`
`compl~ted construction of a vector (designated HuG)
`
`conta-ining a gene coding for the heavy chain ·of an antibody.
`
`Evidence of this wor~ is.contained_in the copies of pages
`. ., . ~ .
`from the laboratory noteb~ok. o:t. TJm :Gadus~ a technician in .
`
`~
`~ ··: •
`my laboratory. wi~h whom Dr. oi worked,· attached he~eto as
`Exhibit E.. Those p'a'g'e~ are :di,te'ct pr_ior to. Qct;;,ober. 19 I 1983.
`
`'
`
`1
`
`-1'
`
`'
`
`'
`
`'
`
`'
`
`..
`
`These vectors contained regulatory sequences making them
`
`suitable for transf·ec_.tion into qrid exp~e.§lsiq:n i.n mamma·lian
`
`cell lines.
`
`6.
`
`Prior· to October 19, ·1983 Dr. Oi accepted a
`
`job at Becton Dickins~~ and·:company. Dr. oi left my
`
`labo:r:atory in November 19S3.:
`
`7.
`
`I. am 'i~formed·and do b~lieve that on November
`
`23,.1983 the HuK and HuG vector~ that Dr. Oi had constructed
`
`were sent to Dr. Morris.on from my laboratory by Tim Gadus.
`
`These materials we::re: typically sent via the Uni-ted states
`
`Postal Servic~, ~egular ~ali. A copy of the transmittal
`
`record evidencin9 this ~hipment. is attached hereto as
`
`. Exhibit F.
`
`8.
`
`I further declare that. ali statements made
`
`herein of my own ·knowledge are true and all statements made
`
`on information a·nd belief are- believed to be true; and
`
`further that these statements were made with the knowledge
`
`3
`
`Merck Ex. 1112, Pg. 18
`
`

`

`,\
`
`~
`
`,_
`
`•••
`
`""-
`
`·~
`
`..
`
`•
`
`that willful, false stat.ements and the like- so made are
`
`punishable by fine or ~mprisonment or both under
`
`Section 1001 of Title 18 of the United States, Code and that
`
`such willful, false statements may jeoparaize the validity
`
`of the· appli~ation or any patent issuing thereon.·
`
`. s
`
`By
`
`' , , .
`
`' • ( "
`
`:
`
`. ~: . '
`
`4
`
`Merck Ex. 1112, Pg. 19
`
`

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